Bibliographic details of the publications referred to by author in this specification are collected alphabetically at the end of the description.
The reference in this specification to any prior publication (or information derived from it), or to any matter which is known, is not, and should not be taken as an acknowledgment or admission or any form of suggestion that that prior publication (or information derived from it) or known matter forms part of the common general knowledge in the field of endeavour to which this specification relates.
The rapidly increasing sophistication of recombinant DNA technology is greatly facilitating research into the medical and veterinary fields. Cytokine research is of particular importance, especially as these molecules regulate the proliferation, differentiation and function of a great variety of cells, such as cells involved in mediating an immune response. Administration of recombinant cytokines or regulating cytokine function and/or synthesis is becoming, increasingly, the focus of medical research into the treatment of a range of disease conditions in humans and animals.
Interferons (IFNs) represent a group of cytokines which cause diverse cellular effects in vertebrates by regulating hundreds of genes known as the IFN stimulated genes (ISG). IFNs exhibit multifunctional roles including the modulation of cellular growth cycles and the induction and regulation of inflammatory responses which largely shape the overall immune response. One of the most recognised attributes of IFNs is their ability to induce cellular resistance to virus (Hwang et al 1995, PNAS).
Vertebrate IFN consists of three types which are classified based on their molecular structure, receptor specificity and the pathways they induce (Smith et al., 2005; Theofilopoulos et al., 2005).
Type I IFN includes IFNα, of which there are multiple representatives in the vertebrate genomes (Meager, 2002), and IFNβ, usually represented by a single gene (Schultz et al., 2004). Type I IFNs are activated upon detection of many viruses (Jacobs and Langland 1996; Majde 2000) and once activated, interact with their receptor, the IFNα/β receptor (IFNα/βR), to induce a subset of the ISG which result in IFN-specific antiviral protection (de Veer et al., 2001; Takaoka and Yanai 2006). The therapeutic application of Type I IFN has been successful in protecting mammals from viruses, including influenza (Beilharz et al., 2007; Koerner et al., 2007), hepatitis C (Marcello et al., 2006) and several other viruses (Kotenko et al., 2003; Sheppard et al., 2003; Meager et al., 2005).
The Type II IFN group consists of a single member, IFNγ (Schroder et al., 2004). IFNγ activates antiviral activity and cellular immunity through the IFNγ receptor (IFN-γR) (Kamijo et al., 1994; Schroder, et al., 2004). This IFN also demonstrates antiviral activity, including protection from Foot and Mouth Disease (FMD) viruses (Moraes et al., 2007), polyomavirus (Abend et al., 2007), and others (Chesler et al., 2003) and has similarly been employed as a therapeutic against a variety of pathogens (Schroder et al., 2004).
Recently a third IFN family has been reported in mammals, Type III IFN, of which there are currently three known subtypes, these being IFNλ1 (also known as IL29), IFNλ2 (also known as IL28A) and IFNλ3 (also known as IL28B) (Sheppard, et al., 2003). The mammalian IFNλ members interact with a distinct receptor complex consisting of the IFNλ receptor 1 (IFNλR1) and the IL10 receptor β (IL10Rβ) (Donnelly et al., 2004). These subunit receptors dimerise upon ligand binding, phosphorylating the signal transducer and activator of transcription factors (STAT) (Kotenko et al., 2003; Donnelly et al., 2004) which results in the activation of an IFNλ-specific gene set (Ank et al., 2006; Marcello et al., 2006). Despite its IL10-like signalling complex (Sheppard et al., 2003; Donnelly et al., 2004) mammalian IFNλ exhibits antiviral properties that resemble Type I IFN (Meager et al., 2005). Hence, it appears that IFNλ may induce a subset of Type I IFN-like genes through an alternative receptor complex (Marcello et al., 2006).
Several investigations of human INFλ (HuIFNλ) have revealed the potential of IFNλ to inhibit virus. For example, HuIFNλII has been demonstrated to inhibit hepatitis C virus in mammalian cell culture (Robek et al., 2005; Marcello et al., 2006). This protection was comparable to Type I IFN, yet distinct gene subsets are initiated by each IFN (Marcello et al., 2006). Thus viral protection could be initiated from a different array of stimulated genes (Rio et al., 1998; Stohr and Esveld, 2004; Meager et al., 2005; Annibali et al., 2007). In addition, comparisons of the antiviral properties of IFNλ and Type I IFN demonstrates that both types of IFN are able to inhibit EMCV. However, the effects largely differed in magnitude (Meager et al., 2005). Similar findings were observed in research involving VSV (Kotenko et al., 2003). This suggests that the INFλ response pathway may be necessary for a specific functional role in certain viral infections.
There has recently been a great deal of concern with regard to poultry viruses with the observed outbreaks of avian influenza which can spread rapidly and cause high morbidity in both poultry and human populations (Stohr and Esveld 2004). The difficult task of managing problem viruses in poultry combined with the fact that associated immunotoxicity effects may be observed with the use of Type I and Type II IFN therapeutics (Kotenko et al., 2003; Stohr and Esveld 2004; Meager et al., 2005) necessitates an ongoing investigation for new and alternative antiviral strategies. Accordingly, there is a need for an improved control of poultry viruses which would benefit the poultry industries as well as help to reduce the risk of transmission of these viruses to humans (Chen et al., 2007). Still further, in light of the importance of the poultry industry to the economics and food supplies of communities world-wide, the development of new means for regulating and improving immunomodulation is of critical importance.
In the work leading up to the present invention, the nucleic acid molecule which encodes chicken IFN-λ (hereinafter referred to as “ChIFN-λ”) has been isolated and sequenced. Recombinant genetic constructs comprising the isolated nucleic acid molecule of the present invention have been produced and expressed in transformed cells, thereby enabling the isolation and sequencing of ChIFN-λ. These findings now provide an opportunity for alternative IFN therapies.